2.3. Systems biology modeling of junctional localization and downstream signaling of the Ang–Tie signaling pathway

摘要: 2.3. 2. Introduction The Angiopoietin (Ang)-Tie signaling pathway is a major endothelial signaling pathway regulating vascular quiescence, permeability, stability, and growth 1, 2. Disrupted Tie2 signaling has been linked to many diseases including cancer 3-5, peripheral arterial disease 6, ocular diseases including diabetic retinopathy and diabetic macular edema 7-9, systemic inflammation 10, 11, and infectious diseases including COVID-19 12, 13. The Ang-Tie signaling pathway consists of multiple ligands, receptors, and molecular regulators and mechanisms that form a complex reaction network. The Ang family of ligands consists of Ang1, Ang2, Ang3, and Ang4. Ang1 is the natural agonist of Tie2, and it is associated with vascular growth and stability 14, 15. Ang2 is primarily considered to be an antagonist of Tie2 and is mostly associated with vascular leakage and inflammation, although it also acts as a context-dependent Tie2 agonist 16-21. Ang1 exists in highly oligomerized forms, whereas Ang2 exists primarily as lower-order multimers (eg, dimers), although higher-order oligomeric forms are observed 22. Multimeric ligands Ang1 and Ang2 are known to induce the multimerization and subsequent activation of Tie2, and the activation of Tie2 requires tetrameric or higher orders of multimerization 22. Ang3 and Ang4 are mouse and human orthologs, respectively, with poorly defined biological functions 23.